Colon cancer remains a leading cause of mortality worldwide, despite the well-characterized molecular events that occur during the progression from adenoma to carcinoma (Meijer et al., J. Clin. Pathol. 51: 901-909 (1998)). Colorectal carcinoma (CRC) is the third most common cancer and the second leading cause of cancer death in Europe and the United States, with 300,000 new cases and 200,000 deaths each year (Midgley et al., Lancet 353: 391-399 (1999)). Oncogenic transformation of colorectal epithelium to form invasive carcinomas is driven by the sequential acquisition of tumor-specific genetic aberrations and chromosomal aneuploidy (Fearon et al., Cell 61: 759-767 (1990); Ried et al., Genes Chromosomes Cancer 15: 234-245 (1996)).
A benign tumor of glandular origin, namely an adenoma, can become malignant over time, at which point it is referred to as an adenocarcinoma. Not all adenomas progress to adenocarcinomas. In fact, only a small subset of adenomas progress to adenocarcinomas.
Genomic instability is a key component of the progression from adenoma to adenocarcinoma. In about 15% of progressions there is a deficiency in the repair of DNA mismatch, which leads to microsatellite instability (designated MSI or MIN) (di Pietro et al., Gastroenterology 129: 1047-1059 (2005)). In the other 85% of progressions there is aneuploidy at the chromosomal level (designated CIN). It has now been well-established that changes in DNA copy number occur in specific patterns and are associated with different clinical behavior (Hermsen et al., Gastroenterology 123: 1109-1119 (2002)).
Chromosomal aberrations involving chromosomes 4, 5, 7, 8, 13, 15, 17, 18 and 20 have been frequently reported in CRC. Progression from adenoma to adenocarcinoma reportedly has been associated with 8p, 13q and 20q gains and 8p, 15q, 17p and 18q losses (Hermsen et al. (2002), supra). The most frequently observed chromosomal aberration in CRC is a gain of 20q, which reportedly occurs in more than 65% of CRC cases (Meijer et al. (1998), supra). Gains of 20q, in particular 20q12-q13, reportedly have been associated with poor outcome in CRC.
Sienna et al. (U.S. Pat. No. 7,635,570 B2, which issued Dec. 22, 2009) disclose the determination of the copy number of the epidermal growth factor receptor (EGFR) gene by fluorescent in situ hybridization (FISH) and quantitative polymerase chain reaction (PCR) on CRC samples. The method is disclosed to be useful for predicting whether an agent that binds EGFR will be efficacious in treating CRC, such as when there is an increase in the copy number of the EGFR gene. The method is also disclosed to be useful for assessing the efficacy of treatment of CRC, wherein a decrease in the copy number of the EGFR gene after treatment indicates that the treatment is effective. Sienna et al. discloses conflicting reports in the art about whether or not over-expression of EGFR can be correlated with prognosis of carcinoma.
Perucho et al. (U.S. Pat. No. 7,090,978 B2, which issued Aug. 15, 2006) disclose the detection of mutations, specifically insertions and deletions, by arbitrarily primed PCR (AP-PCR) to identify tumors, such as colon carcinoma. Vogelstein et al. (U.S. Pat. No. 5,532,108, which issued Jul. 2, 1996, U.S. Pat. No. 5,702,886, which issued Dec. 30, 1997, and U.S. Pat. No. 5,834,190, which issued Nov. 10, 1998) disclose the determination of chromosome 18q loss in the prognosis of patients with TNM (staging system developed by Union Internationale Centre Cancer (UICC) in which T represents primary tumor, N represents regional lymph node involvement, and M represents metastases) stage II and stage III colorectal cancer. Polymorphic genetic markers, such as on chromosome 18q, are amplified from standard formalin-fixed, paraffin-embedded tumor tissue. Vogelstein et al. specifically identifies the DCC (Deleted in Colorectal Carcinomas) gene.
Coignet et al. (U.S. Pat. No. 7,479,370 B2, which issued Jan. 20, 2009) disclose a method of detecting deletions in 13q14 in isolated lymphocytes. The deletions are reportedly associated with acute lymphobloastic leukemia (ALL) and chronic lymphocytic leukemia (CLL).
Gazdar et al. (U.S. Pat. No. 4,892,829, which issued Jan. 9, 1990) disclose a human plasma cell line. The cell line has a rearranged c-myc proto-oncogene (8q24).
Microarray-based gene expression profiling (Habermann et al., Genes Chromosomes & Cancer 46 (1): 10-26 (2007)) and comparative genomic hybridization (CGH) (Meijer et al. (1998), supra; and Hermsen et al., Gastroenterology 123: 1109-1119 (2002)) have been reported to provide progression pathways from colorectal adenoma to carcinoma. More recently, microRNA (miRNA) analysis has been reported to demonstrate that increased expression of the miR-17-92 cluster occurs during progression from colorectal adenoma to adenocarcinoma, and that increased expression is associated with a DNA copy number gain of the miR17-92 locus on 13q31 and c-myc expression.
Rava et al. (U.S. Pat. App. Pub. No. US 2013/0034546 A1, published Feb. 7, 2013) discloses a method for determining copy number variation (CNV) of a sequence of interest in a test sample. The method involves computational analysis of sequence reads of nucleic acids in the test sample. The analysis involves comparison of the sequence reads to chromosomal segments of interest, such as segments known to contain one or more oncogenes and/or one or more tumor suppressor genes. Aneuploidies can comprise an amplification of one or more regions, such as 20q13, 19q12, 1q21-1q23, 8p11-8p12, and 17q12, and can comprise a gene, such as MYC, ERBB2, CCND1, FGFR1, FGFR2, HRAS, KRAS, MYB, MDM2, CCNE, KRAS, MET, ERBB1, CDK4, MYCB, AKT2, MDM2, and CDK4. The cancer can be colorectal cancer.
Cowens et al. (U.S. Pat. App. Pub. No. US 2011/0097759 A1, published Apr. 28, 2011) discloses a method of predicting the clinical outcome in a subject diagnosed with colorectal cancer. The method comprises determining evidence of the expression of one or more predictive RNA transcripts or their expression products.
Pinto Morais de Carvalho et al. (U.S. Pat. App. Pub. No. US 2011/0236396 A1, published Sep. 29, 2011) discloses methods and compositions for diagnosing colorectal adenocarcinoma associated with a chromosomal aberration on chromosome 20q or a predisposition for developing such an adenocarcinoma by determining the expression levels of a set of marker genes. The method comprises detecting in a sample elevated expression levels of at least the marker genes RNPC1 and TCFL5.
Meijer et al. (U.S. Pat. App. Pub. No. 2010/0304374 A1, published Dec. 2, 2010) discloses an in vitro method for detecting the presence of colorectal adenocarcinoma cells. The method comprises detecting in a test sample elevated expression of at least the marker genes NM_017495 and NM_006602, both of which occur on chromosome 20q. The method can further comprise detecting elevated expression of NM_018840, NM_003600, NM_018270, NM_007002, and NM_016397, all of which occur on chromosome 20q. The method can comprise detecting in a test sample elevated expression of various other combinations of marker genes, such as at least 12 of Table 1, at least one of Table 17, two or more of Table 2 (8p), one or more of Table 3 (8q), three or more of Table 4 (13q), one or more of Table 5 (15q), one or more of Table 6 (17p), three or more of Table 7 (18q), nine or more of Table 8 (20q), two or more of Table 9 (20q), or at least one of Table 2 (8p), Table 3 (8q), Table 4 (13), Table 5 (15q), Table 6 (17p), Table 7 (18q), and either of Table 8 or 9 (20q).
It is clinically important to identify the progression of colorectal adenoma to adenocarcinoma as early as possible, in order to allow early-stage treatment, desirably in the absence of surgical intervention. In view of the foregoing, it is an object of the present disclosure to provide materials and methods to prognosticate, e.g., assess risk of progression, of colorectal adenoma. The materials and related methods can be used to assess potential responsiveness to treatment with a therapeutic agent, thereby enabling selection of a therapeutic agent for targeted treatment, monitor recurrence, and assess efficacy of therapeutic treatment of colorectal adenocarcinoma. Other objects and advantages, as well as inventive features, will become apparent from the detailed description provided herein.